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Discovery of potent and selective PARP-1 and PARP-2 inhibitors: SBDD analysis via a combination of X-ray structural study and homology modeling.
Bioorg Med Chem. 2006 Mar 01; 14(5):1378-90.BM

Abstract

We disclose herein our efforts aimed at discovery of selective PARP-1 and PARP-2 inhibitors. We have recently discovered several novel classes of quinazolinones, quinazolidinones, and quinoxalines as potent PARP-1 inhibitors, which may represent attractive therapeutic candidates. In PARP enzyme assays using recombinant PARP-1 and PARP-2, the quinazolinone derivatives displayed relatively high selectivity for PARP-1 and quinoxaline derivatives showed superior selectivity for PARP-2, and the quinazolidinone derivatives did not have selectivity for PARP-1/2. Structure-based drug design analysis via a combination of X-ray structural study utilizing the complexes of inhibitors and human PARP-1 catalytic domain, and homology modeling using murine PARP-2 suggested distinct interactions of inhibitors with PARP-1 and PARP-2. These findings provide a new structural framework for the design of selective inhibitors for PARP-1 and PARP-2.

Authors+Show Affiliations

Ishida J
Medicinal Chemistry Research Laboratories, Fujisawa Pharmaceutical Co. Ltd, Tsukuba, Ibaraki, Japan.
Yamamoto H
No affiliation info available
Kido Y
No affiliation info available
Kamijo K
No affiliation info available
Murano K
No affiliation info available
Miyake H
No affiliation info available
Ohkubo M
No affiliation info available
Kinoshita T
No affiliation info available
Warizaya M
No affiliation info available
Iwashita A
No affiliation info available
Mihara K
No affiliation info available
Matsuoka N
No affiliation info available
Hattori K
No affiliation info available

MeSH

Binding SitesCatalytic DomainEnzyme InhibitorsHumansModels, ChemicalModels, MolecularPoly (ADP-Ribose) Polymerase-1Poly(ADP-ribose) Polymerase InhibitorsPoly(ADP-ribose) PolymerasesQuinazolinesQuinoxalinesStructure-Activity Relationship

Pub Type(s)

Journal Article

Language

eng

PubMed ID

16288880

Citation

Ishida, Junya, et al. "Discovery of Potent and Selective PARP-1 and PARP-2 Inhibitors: SBDD Analysis Via a Combination of X-ray Structural Study and Homology Modeling." Bioorganic & Medicinal Chemistry, vol. 14, no. 5, 2006, pp. 1378-90.
Ishida J, Yamamoto H, Kido Y, et al. Discovery of potent and selective PARP-1 and PARP-2 inhibitors: SBDD analysis via a combination of X-ray structural study and homology modeling. Bioorg Med Chem. 2006;14(5):1378-90.
Ishida, J., Yamamoto, H., Kido, Y., Kamijo, K., Murano, K., Miyake, H., Ohkubo, M., Kinoshita, T., Warizaya, M., Iwashita, A., Mihara, K., Matsuoka, N., & Hattori, K. (2006). Discovery of potent and selective PARP-1 and PARP-2 inhibitors: SBDD analysis via a combination of X-ray structural study and homology modeling. Bioorganic & Medicinal Chemistry, 14(5), 1378-90.
Ishida J, et al. Discovery of Potent and Selective PARP-1 and PARP-2 Inhibitors: SBDD Analysis Via a Combination of X-ray Structural Study and Homology Modeling. Bioorg Med Chem. 2006 Mar 1;14(5):1378-90. PubMed PMID: 16288880.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Discovery of potent and selective PARP-1 and PARP-2 inhibitors: SBDD analysis via a combination of X-ray structural study and homology modeling. AU - Ishida,Junya, AU - Yamamoto,Hirofumi, AU - Kido,Yoshiyuki, AU - Kamijo,Kazunori, AU - Murano,Kenji, AU - Miyake,Hiroshi, AU - Ohkubo,Mitsuru, AU - Kinoshita,Takayoshi, AU - Warizaya,Masaichi, AU - Iwashita,Akinori, AU - Mihara,Kayoko, AU - Matsuoka,Nobuya, AU - Hattori,Kouji, Y1 - 2005/11/08/ PY - 2005/05/16/received PY - 2005/09/26/revised PY - 2005/09/27/accepted PY - 2005/11/18/pubmed PY - 2006/5/4/medline PY - 2005/11/18/entrez SP - 1378 EP - 90 JF - Bioorganic & medicinal chemistry JO - Bioorg Med Chem VL - 14 IS - 5 N2 - We disclose herein our efforts aimed at discovery of selective PARP-1 and PARP-2 inhibitors. We have recently discovered several novel classes of quinazolinones, quinazolidinones, and quinoxalines as potent PARP-1 inhibitors, which may represent attractive therapeutic candidates. In PARP enzyme assays using recombinant PARP-1 and PARP-2, the quinazolinone derivatives displayed relatively high selectivity for PARP-1 and quinoxaline derivatives showed superior selectivity for PARP-2, and the quinazolidinone derivatives did not have selectivity for PARP-1/2. Structure-based drug design analysis via a combination of X-ray structural study utilizing the complexes of inhibitors and human PARP-1 catalytic domain, and homology modeling using murine PARP-2 suggested distinct interactions of inhibitors with PARP-1 and PARP-2. These findings provide a new structural framework for the design of selective inhibitors for PARP-1 and PARP-2. SN - 0968-0896 UR - https://www.unboundmedicine.com/medline/citation/16288880/Discovery_of_potent_and_selective_PARP_1_and_PARP_2_inhibitors:_SBDD_analysis_via_a_combination_of_X_ray_structural_study_and_homology_modeling_ DB - PRIME DP - Unbound Medicine ER -